Critical Role of l-Arginine in Endothelial Cell Survival During Oxidative Stress

Background— Oxidative damage of vascular endothelium represents an important initiation step in the development of atherosclerosis. Recently, we reported about protection of inducible nitric oxide synthase (iNOS)-derived high-output NO in endothelial cells. Because iNOS activity critically depends on the availability of its substrate l-arginine, the present study aims at elucidating iNOS-mediated effects on H2O2-induced apoptosis of cytokine-activated rat aortic endothelial cells (AECs) subject to medium l-arginine concentrations. Methods and Results— In cytokine-activated AECs, iNOS activity was found to be half-maximal at 60 μmol/L arginine, which represents the medium serum level in rats but also in humans. Maximal activity is seen at and above 200 μmol/L arginine. Activated cells grown in the absence of arginine with minimal iNOS activity are highly sensitive toward H2O2-induced apoptosis, and increases in medium arginine concentrations result in increased cell survival. Moreover, competition experime...